6hcu - Revision history

OCA at 06:51, 17 April 2019

OCA — Wed, 17 Apr 2019 06:51:25 GMT

←Older revision		Revision as of 06:51, 17 April 2019
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	<StructureSection load='6hcu' size='340' side='right'caption='[[6hcu]], [[Resolution\|resolution]] 1.62Å' scene=''>		<StructureSection load='6hcu' size='340' side='right'caption='[[6hcu]], [[Resolution\|resolution]] 1.62Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6hcu]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6HCU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6HCU FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6hcu]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Plaf7 Plaf7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6HCU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6HCU FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FYB:~{N}-[[4,4-bis(fluoranyl)-1-oxidanyl-cyclohexyl]methyl]-6-fluoranyl-4-oxidanylidene-chromene-2-carboxamide'>FYB</scene>, <scene name='pdbligand=HIS:HISTIDINE'>HIS</scene>, <scene name='pdbligand=LYS:LYSINE'>LYS</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=TRS:2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>TRS</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FYB:~{N}-[[4,4-bis(fluoranyl)-1-oxidanyl-cyclohexyl]methyl]-6-fluoranyl-4-oxidanylidene-chromene-2-carboxamide'>FYB</scene>, <scene name='pdbligand=HIS:HISTIDINE'>HIS</scene>, <scene name='pdbligand=LYS:LYSINE'>LYS</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=TRS:2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>TRS</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PF3D7_1350100 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=36329 PLAF7])</td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Lysine--tRNA_ligase Lysine--tRNA ligase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=6.1.1.6 6.1.1.6] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Lysine--tRNA_ligase Lysine--tRNA ligase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=6.1.1.6 6.1.1.6] </span></td></tr>
	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6hcu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6hcu OCA], [http://pdbe.org/6hcu PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6hcu RCSB], [http://www.ebi.ac.uk/pdbsum/6hcu PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6hcu ProSAT]</span></td></tr>		<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6hcu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6hcu OCA], [http://pdbe.org/6hcu PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6hcu RCSB], [http://www.ebi.ac.uk/pdbsum/6hcu PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6hcu ProSAT]</span></td></tr>
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	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: Lysine--tRNA ligase]]		[[Category: Lysine--tRNA ligase]]
		+	[[Category: Plaf7]]
	[[Category: Baragana, B]]		[[Category: Baragana, B]]
	[[Category: Forte, B]]		[[Category: Forte, B]]

OCA at 06:57, 3 April 2019

OCA — Wed, 03 Apr 2019 06:57:55 GMT

←Older revision		Revision as of 06:57, 3 April 2019
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-	'''Unreleased structure'''

-	~~The entry~~ 6hcu is ~~ON HOLD until Paper~~ Publication	+	==Crystal Structure of Lysyl-tRNA Synthetase from Plasmodium falciparum bound to a difluoro cyclohexyl chromone ligand==
		+	<StructureSection load='6hcu' size='340' side='right'caption='[[6hcu]], [[Resolution\|resolution]] 1.62Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[6hcu]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6HCU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6HCU FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FYB:~{N}-[[4,4-bis(fluoranyl)-1-oxidanyl-cyclohexyl]methyl]-6-fluoranyl-4-oxidanylidene-chromene-2-carboxamide'>FYB</scene>, <scene name='pdbligand=HIS:HISTIDINE'>HIS</scene>, <scene name='pdbligand=LYS:LYSINE'>LYS</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=TRS:2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>TRS</scene></td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Lysine--tRNA_ligase Lysine--tRNA ligase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=6.1.1.6 6.1.1.6] </span></td></tr>
		+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6hcu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6hcu OCA], [http://pdbe.org/6hcu PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6hcu RCSB], [http://www.ebi.ac.uk/pdbsum/6hcu PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6hcu ProSAT]</span></td></tr>
		+	</table>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Malaria and cryptosporidiosis, caused by apicomplexan parasites, remain major drivers of global child mortality. New drugs for the treatment of malaria and cryptosporidiosis, in particular, are of high priority; however, there are few chemically validated targets. The natural product cladosporin is active against blood- and liver-stage Plasmodium falciparum and Cryptosporidium parvum in cell-culture studies. Target deconvolution in P. falciparum has shown that cladosporin inhibits lysyl-tRNA synthetase (PfKRS1). Here, we report the identification of a series of selective inhibitors of apicomplexan KRSs. Following a biochemical screen, a small-molecule hit was identified and then optimized by using a structure-based approach, supported by structures of both PfKRS1 and C. parvum KRS (CpKRS). In vivo proof of concept was established in an SCID mouse model of malaria, after oral administration (ED90 = 1.5 mg/kg, once a day for 4 d). Furthermore, we successfully identified an opportunity for pathogen hopping based on the structural homology between PfKRS1 and CpKRS. This series of compounds inhibit CpKRS and C. parvum and Cryptosporidium hominis in culture, and our lead compound shows oral efficacy in two cryptosporidiosis mouse models. X-ray crystallography and molecular dynamics simulations have provided a model to rationalize the selectivity of our compounds for PfKRS1 and CpKRS vs. (human) HsKRS. Our work validates apicomplexan KRSs as promising targets for the development of drugs for malaria and cryptosporidiosis.

-	~~Authors: Tamjar, J~~., Robinson, D.A., ~~Baragana~~, B., ~~Norcross~~, N., ~~Forte~~, B., ~~Walpole~~, C., Gilbert, I.H.	+	Lysyl-tRNA synthetase as a drug target in malaria and cryptosporidiosis.,Baragana B, Forte B, Choi R, Nakazawa Hewitt S, Bueren-Calabuig JA, Pisco JP, Peet C, Dranow DM, Robinson DA, Jansen C, Norcross NR, Vinayak S, Anderson M, Brooks CF, Cooper CA, Damerow S, Delves M, Dowers K, Duffy J, Edwards TE, Hallyburton I, Horst BG, Hulverson MA, Ferguson L, Jimenez-Diaz MB, Jumani RS, Lorimer DD, Love MS, Maher S, Matthews H, McNamara CW, Miller P, O'Neill S, Ojo KK, Osuna-Cabello M, Pinto E, Post J, Riley J, Rottmann M, Sanz LM, Scullion P, Sharma A, Shepherd SM, Shishikura Y, Simeons FRC, Stebbins EE, Stojanovski L, Straschil U, Tamaki FK, Tamjar J, Torrie LS, Vantaux A, Witkowski B, Wittlin S, Yogavel M, Zuccotto F, Angulo-Barturen I, Sinden R, Baum J, Gamo FJ, Maser P, Kyle DE, Winzeler EA, Myler PJ, Wyatt PG, Floyd D, Matthews D, Sharma A, Striepen B, Huston CD, Gray DW, Fairlamb AH, Pisliakov AV, Walpole C, Read KD, Van Voorhis WC, Gilbert IH Proc Natl Acad Sci U S A. 2019 Mar 20. pii: 1814685116. doi:, 10.1073/pnas.1814685116. PMID:30894487<ref>PMID:30894487</ref>

-	~~Description: Crystal Structure~~ of ~~Lysyl~~-~~tRNA Synthetase from Plasmodium falciparum bound to a difluoro cyclohexyl chromone ligand~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased~~ Structures]]	+	</div>
-	[[Category: ~~Tamjar, J~~]]	+	<div class="pdbe-citations 6hcu" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Lysine--tRNA ligase]]
	[[Category: Baragana, B]]		[[Category: Baragana, B]]
-	[[Category: Gilbert, I.H]]
-	[[Category: Robinson, D.A]]
	[[Category: Forte, B]]		[[Category: Forte, B]]
		+	[[Category: Gilbert, I H]]
	[[Category: Norcross, N]]		[[Category: Norcross, N]]
		+	[[Category: Robinson, D A]]
		+	[[Category: Tamjar, J]]
	[[Category: Walpole, C]]		[[Category: Walpole, C]]
		+	[[Category: Adenylyltransferase activity]]
		+	[[Category: Ligase]]
		+	[[Category: Transferase]]
		+	[[Category: Trna binding]]

OCA at 05:20, 6 March 2019

OCA — Wed, 06 Mar 2019 05:20:42 GMT

←Older revision		Revision as of 05:20, 6 March 2019
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6hcu is ON HOLD	+	The entry 6hcu is ON HOLD until Paper Publication

	Authors: Tamjar, J., Robinson, D.A., Baragana, B., Norcross, N., Forte, B., Walpole, C., Gilbert, I.H.		Authors: Tamjar, J., Robinson, D.A., Baragana, B., Norcross, N., Forte, B., Walpole, C., Gilbert, I.H.
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	Description: Crystal Structure of Lysyl-tRNA Synthetase from Plasmodium falciparum bound to a difluoro cyclohexyl chromone ligand		Description: Crystal Structure of Lysyl-tRNA Synthetase from Plasmodium falciparum bound to a difluoro cyclohexyl chromone ligand
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
		+	[[Category: Tamjar, J]]
		+	[[Category: Baragana, B]]
		+	[[Category: Gilbert, I.H]]
	[[Category: Robinson, D.A]]		[[Category: Robinson, D.A]]
	[[Category: Forte, B]]		[[Category: Forte, B]]
	[[Category: Norcross, N]]		[[Category: Norcross, N]]
	[[Category: Walpole, C]]		[[Category: Walpole, C]]
-	[[Category: Tamjar, J]]
-	[[Category: Baragana, B]]
-	[[Category: Gilbert, I.H]]

OCA: Protected "6hcu" [edit=sysop:move=sysop]

OCA — Wed, 22 Aug 2018 04:57:49 GMT

Protected "6hcu" [edit=sysop:move=sysop]

←Older revision

Revision as of 04:57, 22 August 2018

OCA: New page: '''Unreleased structure''' The entry 6hcu is ON HOLD Authors: Tamjar, J., Robinson, D.A., Baragana, B., Norcross, N., Forte, B., Walpole, C., Gilbert, I.H. Description: Crystal Structu...

OCA — Wed, 22 Aug 2018 04:57:48 GMT

New page: '''Unreleased structure''' The entry 6hcu is ON HOLD Authors: Tamjar, J., Robinson, D.A., Baragana, B., Norcross, N., Forte, B., Walpole, C., Gilbert, I.H. Description: Crystal Structu...

New page

'''Unreleased structure'''

The entry 6hcu is ON HOLD

Authors: Tamjar, J., Robinson, D.A., Baragana, B., Norcross, N., Forte, B., Walpole, C., Gilbert, I.H.

Description: Crystal Structure of Lysyl-tRNA Synthetase from Plasmodium falciparum bound to a difluoro cyclohexyl chromone ligand
[[Category: Unreleased Structures]]
[[Category: Robinson, D.A]]
[[Category: Forte, B]]
[[Category: Norcross, N]]
[[Category: Walpole, C]]
[[Category: Tamjar, J]]
[[Category: Baragana, B]]
[[Category: Gilbert, I.H]]